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Approximately 1 million breast cancer cases are diagnosed annually worldwide, with about 17% (n = 170,000) being triple-negative breast cancer (TNBC).

 Most TNBCs, about 75%, have been considered “basal-like,” meaning their expression signature has been shown to be comparable to that of the basal/myoepithelial cells of the breast, with transcriptomic characteristics similar to tumors arising in BRCA1 germline mutation carriers;

 however, more recently, genomic analysis has shown TNBCs to have substantial transcriptional, mutational, and copy number heterogeneity, indicating these tumors are significantly more heterogeneous than previously thought.

 Such findings have helped spur new developments in treating patients with TNBC, a cancer field that has seen relatively few meaningful clinical advancements since the introduction of adjuvant taxane therapy approximately 20 years ago.

 Commonly Accepted Molecular Subtypes of TNBC Based on Gene expression Profiling

 discussion led by Adam M. Brufsky, MD, PhD, experts in breast malignancies reviewed some exciting new developments in TNBC. The discussion focused on 

 testing and other predictive biomarkers and on the promise of 2 novel treatment approaches currently under investigation for TNBC: immunotherapy and anti-body—drug conjugates.

The complexity of TNBCs is increasingly being understood as gene expression profiling is revealing more subtypes. “We’re learning over the last couple of years that these really are likely a collection of multiple different diseases,” said Brufsky. The most recent classification, which revised a widely accepted earlier classification by the same investigators, breaks them into 4 tumor-specific subtypes: 2 basal-like (BL1 and BL2), a mesenchymal (M), and a luminal androgen receptor (LAR) subtype (

 When using these subtypes to assess response to neoadjuvant chemotherapy, significant differences between patient groups have been observed, with a pathological complete response (pCR) found in 41% of BL1 patients, 29% of LAR patients, and 18% of BL2 patients.

 The relevance of these subtypes has yet to be elucidated in prospective studies, and these subtypes have the potential to guide patient selection with regard to some of the newer treatments that are being investigated in clinical trials, including immunotherapy and antibody—drug conjugates.

BL indicates basal-like; LAR, luminal androgen receptor; M, mesenchymal. 

 mutation status, which has been associated with an increased response to platinum agents and poly (ADP-ribose) polymerase (PARP) inhibitors, is the only biomarker that is being used in routine clinical practice to guide treatment. The NCCN Guidelines recommend 

 mutation screening in any patient who develops TNBC at ≤60 years, regardless of family history or other risk factors.

 This is partially because BRCA status has been strongly correlated with TNBC, with 80% of 

 mutation carriers developing TNBC. However, the likelihood of BRCA mutations decreases with advancing age (present in 43.8% of those <40 years vs 16.6% of those >70 years).

 Although some panelists found this recommendation “pretty reasonable,” it doesn’t fully clarify the testing of patients over 60 years old with TNBC, which was a point of discussion during the Peer Exchange

“In an Ashkenazi woman, you could potentially go up even older,” said Mark E. Robson, MD, who said he was liberal about testing but acknowledged it might not be possible to test older non-Jewish women who are on Medicare. The increased leeway with testing Ashkenazi Jewish women is rooted in their significantly increased risk of TNBC and 

 mutations compared with other populations. In one study, 50% of Ashkenazi Jewish women were found to have 

 In contrast, BRCA mutation prevalence in African-American women, another TNBC high-risk group, was less than half that at 20.4%.

 Panelist Aditya Bardia, MBBS, MPH, appeared to be less liberal with 

 testing. “If there’s a clinical indication to do BRCA testing or an indication in terms of a clinical trial, we would consider that, but we don’t do it for everyone with TNBC,” he said. Kimberly L. Blackwell, MD, said she would test regardless of age in the first line to ensure that opportunity to participate in a clinical trial is not missed.

 testing are used to guide treatment, often directing which patients go on to receive immediate platinum-based chemotherapy, but Blackwell said she felt this common practice ultimately limits patients’ options. “What I’m seeing in my referral patterns is that for people who have TNBC, in particular 

 mutations, there’s a rush to put them on a platinum-based chemotherapy and then send them to a place for trial, but I’m really trying to encourage referring physicians to think twice about the 

 mutation carriers so that they get these patients enrolled in a study before they use a platinum-based agent. For the most part, I’d say that over half of the 

-mutation randomized studies require patients to be platinum naïve,” she said. She prefers to reserve platinum-based agents for the second- and third-line settings whenever possible.

Patients with the M subtype, which has a high prevalence of immune-infiltrated lymphocytes, have been thought to be especially primed to benefit from programmed death-ligand 1 (PD-L1) inhibition, and patients with TNBC are quickly being enrolled in checkpoint inhibitor trials, regardless of subtype, because predictive biomarkers have yet to be identified in this setting. “I’m encouraging my patients to participate in both the KEYNOTE studies and some of the single-arm phase I/II studies where the checkpoint inhibitors are being compared,” said Blackwell, who noted many checkpoint inhibitor trials are available and enrolling patients (Table 2).

 Checkpoint Inhibitor Trials Evaluating Patients With TNBC

Trial is ongoing but not recruiting participants. ER+ indicates estrogen receptor positive; PD-L1, programmed death-ligand 1; TNBC, triple-negative breast cancer.

“There’s definitely a signal in a population of patients, but I don’t think we’ve figured out who those patients are, so, unfortunately, we’ve gone back to old-school clinical trial design, which enrolls a lot of people to standard of care versus the immuno-oncology agent,” said Blackwell, noting she remains excited but somewhat guarded about the promise of checkpoint inhibition in TNBC.

Another factor that has been thought to make TNBCs more suitable for immunotherapy when compared with other breast cancer subtypes is the high mutational load of these tumors. In neoadjuvant studies, immune-cell infiltrates have been correlated with responses and long-term outcomes, lending evidence that TNBCs may be more immunogenic.

 But the panelists noted that the mutational picture of these tumors is not fully in line with the characteristics that have previously been tied to improved response. “If you look at the types of mutations that are in the diseases that are most associated with response, they tend to be point mutations and small [insertions or deletions], and so they’re generating abnormal proteins, which can be recognized, whereas in the homologous recombination deficient tumors [including 

 defects], you’ve got big gains and losses [of large chromosomal regions],” said Robson.

Bardia concurred with the other panelists’ cautious optimism. “There’s definitely excitement about immunotherapy, and it works for a subset of patients, but the challenge is we haven’t found that subset,” he said. “The first step is obviously to look at PD-L1, but that might not be the answer. It could be mutation burden of the tumor, and it could be other antigens that are expressed by the tumor, so what the field needs is predictive biomarkers that can show who is going to bene t from immunotherapy.”

Like immunotherapy, antibody—drug conjugates represent another class of medications that have the potential to change the TNBC treatment land- scape. Development of these agents for TNBC was inspired by the success of trastuzumab conjugated to emtansine (T-DM1) in HER2-positive breast cancer. “The idea is that you have an antibody that binds to the cancer cells and then releases chemo only to the cancer cells while sparing the normal cells, which has a better risk pro le by enabling very high doses of chemotherapy to be delivered only to cancer cells,” Bardia said.

An antibody—drug conjugate being developed for TNBC is sacituzumab govitecan (IMMU-132), which binds to tumor-associated calcium signal transducer 2 (Trop-2), a cell-surface glycoprotein that is overexpressed in approximately 85% of TNBCs. “We observed an impressive objective response rate of about 30% and a median progression-free survival [PFS] of about 6 months in patients who had been heavily pretreated,” Bardia said. The patients in the study had received a median of 5 prior lines of therapy. The median overall survival was 16.6 months; 2 patients had complete responses, and tumor shrinkage was observed in 1 patient who had disease progression while on checkpoint inhibitors.

 “In that heavily pretreated population, it was quite encouraging to see the signal,” Bardia said. Based on the results, the FDA granted sacituzumab govitecan a breakthrough therapy designation. Other trials are planned but are not yet recruiting: sacituzumab govitecan with or without carboplatin (NCT02161679) and sacituzumab govitecan for refractory/relapsed TNBC (NCT02574455).

Other antibody—drug conjugates in development for TNBC that were not discussed during the Peer Exchange

 include SGN-LIV1A, an LIV-1-targeted monoclonal antibody linked to the cytotoxin monomethyl auristatin E (MMAE) by a protease-cleavable linker, and glembatumumab vedotin (CDX-011), which targets transmembrane glycoprotein NMB and is also conjugated to MMAE.

 During the recent 2016 San Antonio Breast Cancer Symposium, study investigators reported interim data from an ongoing phase I clinical trial of SGN-LIV1A, which revealed a partial response in 37% of patients (n = 11), a disease control rate of 67%, and a clinical bene t rate of 47%.

 The median PFS was 12 weeks, but 7 patients remained on treatment.

 All patients were heavily pretreated. A safety study of SGN-LIV1A is currently recruiting (NCT01969643).

The results for glembatumumab vedotin appear promising in individuals with tumors that have a high level of glycoprotein NMB expression. In the randomized phase II EMERGE study, the overall objective response rate was only 6% versus 7% for investigator-selected chemotherapy; however, response rates reached 30% in patients with glycoprotein NMB expression in ≥25% of tumor cells.

 Response rates were also significantly improved in patients with TNBC, reaching 18% in this population overall, and 40% when considering those with glycoprotein NMB-overexpressing TNBC. Glembatumumab vedotin is being assessed for metastatic TNBC in the pivotal METRIC study (NCT01997333).

The treatment landscape of TNBC is finally evolving as these tumors and their complex genomic profiles are becoming better understood, Bardia concluded. Clinical trials are essential for these patients, including in the metastatic setting, and should not be overlooked, Blackwell said. “All of us who have busy practices dread the rigmarole that’s involved in putting people on trial, but it’s so worth it to give these options to our patients facing meta- static disease,” she said.

In addition to finding important new treatments and giving hope to patients with advanced disease, clinical trials are helping to find predictive biomarkers that can improve treatment selection for future patients. As a clearer picture of TNBC emerges, treatment sequencing will become an increasingly important piece of the puzzle. “We need to start thinking about the deepest possible characterization of patients, both from a genomic level and potentially from a germline level, so that we can figure out which is the best way of putting these things together for each individual patient,” Robson concluded.

Anders CK, Carey LA. Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer. 

 2009;9(suppl 2):S73-S81. doi: 10.3816/CBC.2009.s.008.

Rakha EA, Reis-Filho JS, Ellis IO. Basal-like breast cancer: a critical review. 

 2008;26(15): 2568-2581. doi: 10.1200/ JCO.2007.13.1748.

Jiang T, Shi W, Natowicz R, et al. Statistical measures of transcriptional diversity capture genomic heterogeneity of cancer. 

. 2014;15:876. doi: 10.1186/1471-2164-15-876.

Székely B, Silber AL, Pusztai L. New therapeutic strategies for triple-negative breast cancer. Cancer Network. UBM Medica Network website. www.cancernetwork.com/oncology-journal/new-therapeutic-strategies-triple-negative-breast-cancer. Published February 15, 2017. Accessed February 26, 2017.

Lehmann BD, Jovanović B, Chen X, et al. Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection. 

. 2016;11(6):e0157368. doi: 10.1371/journal.pone.0157368.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Breast Cancer. Version 2.2016. www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed February 25, 2017.

Greenup R, Buchanan A, Lorizio W, et al. Prevalence of BRCA mutations among women with triple-negative breast cancer (TNBC) in a genetic counseling cohort. 

 2013;20(10):3254-3258. doi: 10.1245/s10434-013-3205-1.

Ono M, Tsuda H, Shimizu C, et al. Evaluation of tumor-infiltrating lymphocytes (TIL) and tumor cell apoptosis as predictive markers for response to neoadjuvant chemotherapy in triple-negative breast cancer. Abstract 559. 

. 2009;27:15s. http://meetinglibrary.asco.org/content/34203-65. Accessed February 25, 2017.

Jochems C, Schlom J. Tumor-infiltrating immune cells and prognosis: the potential link between conventional cancer therapy and immunity. 

 (Maywood). 2011;236(5):567-579. doi: 10.1258/ebm.2011.011007.

Bardia A, Diamond JR, Mayer IA, et al. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of relapsed/refractory, metastatic triple-negative breast cancer: updated results. 2016 San Antonio Breast Cancer Symposium; December 9, 2016; San Antonio, TX. Abstract P4-22-15.

Seattle Genetics highlights phase 1 data for novel antibody-drug conjugate SGN-LIV1A in Patients with Metastatic Breast Cancer at San Antonio Breast Cancer Symposium [news release]. Both- ell, WA; Seattle Genetics. http://investor.seattlegenetics.com/ phoenix.zhtml?c=124860&p=irol-newsArticle_pf&ID=2228848. Accessed February 28, 2017.

Yardley DA, Weaver R, Melisko ME, et al. EMERGE: a randomized phase II study of the antibody-drug conjugate glembatumumab vedotin in advanced glycoprotein NMB-expressing breast cancer. 

 2015;33(14):1609-1619. doi: 10.1200/ JCO.2014.56.2959.

Articles

In an OncLive Peer Exchange® discussion, experts in breast malignancies reviewed some exciting new developments in TNBC.

The Hunt for Biomarkers and Better Treatments in Advanced TNBC

BGB-3111, a second-generation Bruton tyrosine kinase (BTK) inhibitor, is being tested in patients with refractory B-cell lymphoid malignancies in an effort to determine whether the novel oral small molecule is a viable therapeutic option and to better understand its pharmacologic properties. Investigators also are seeking to differentiate BGB-3111 from ibrutinib (Imbruvica), the first and thus far only FDA-approved BTK inhibitor.

BGB-3111 is a potent, irreversible, and highly selective BTK inhibitor that blocks the signaling that leads to growth inhibition and cell death in malignant B cells. “The mechanism is the same as ibrutinib, but with less off-target kinase activity,” said Constantine S. Tam, MBBS, MD, a hematologist at the Peter MacCallum Cancer Centre in Melbourne, Australia, in an e-mail interview. Tam is the principal investigator for the trial.

Tam said that investigators are targeting “the diseases known to be sensitive to ibrutinib, such as chronic lymphocytic leukemia [CLL], follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinemia, and activated B-cell like—diffuse large B-cell lymphoma.”

If successful, BGB-3111 could fulfill a need for a more concentrated therapy to treat patients with chemotherapy-refractory B-cell malignancies and patients in frontline settings who are not good candidates for chemotherapy, according to Tam.

Results from preclinical biochemical and cellular assays show that BGB-3111 has similar potency for BTK inhibition compared with ibrutinib while being less active than ibrutinib against other kinase targets including EGFR, ITK, JAK3, HER2, and TEC.

 This is reflected in the higher BGB-3111 dose required to inhibit half of the off-target enzymatic activity compared with ibrutinib; a 2- to 70-fold higher concentration of BGB-3111 versus ibrutinib is needed to achieve similar levels of inhibition in other targets. Therefore, BGB-3111 appears to be associated with less toxicity.

In early findings from a safety analysis of the ongoing phase I trial reported at the 2016 American Society of Hematology Annual Meeting, the objective response rate (ORR) with BGB-3111 therapy was 96% among patients with CLL and small lymphocytic leukemia (SLL).

 The cutoff date for this analysis was October 3, 2016.

The ORR with BGB-3111 consisted of partial responses (PRs; 67%) and PRs with lymphocytosis (28%). In those with high-risk molecular characteristics (del17p and/or del11q; n = 17), the ORR was 100%.

At the time of reporting, 66 patients with CLL or SLL had received BGB-3111 at escalating doses starting at 40 to 160 mg twice daily. The analysis included 46 patients with at least 12 weeks of follow-up; the median duration of follow-up was 8.6 months.

Tam and colleagues reported that none of the patients treated experienced progressive disease or Richter transformation. The most common all-grade adverse events (AEs) were contusion/petechiae/purpura (48%), upper respiratory tract infection (33%), fatigue (28%), cough (20%), diarrhea (20%), headache (20%), muscle spasms (17%), nausea (15%), arthralgia (13%), dizziness (11%), constipation (11%), neutropenia (11%), and rash (11%).

Tam said that the AEs with BGB-3111, including arthralgia, easy bruising, and delayed wound healing, are similar to those seen with ibrutinib but at a low frequency.

Most patients have no significant AEs,” Tam said. “We are happy with the very high drug exposures reached in this study, approximately 8 to 10 times higher than ibrutinib, and the favorable AE profile despite these very high drug doses, due to the specificity of the drug. We will be interested to know if this high drug level translates to better clinical efficacy than ibrutinib in head-to-head studies.”

Next steps for this research include phase III studies comparing the efficacy of BGB-3111 with ibrutinib. One study currently underway is randomizing participants with MYD88 mutation—positive Waldenström macroglobulinemia to BGB-3111 versus ibrutinib; a third arm will administer BGB-3111 monotherapy to patients with wild-type disease (NCT03053440).

BGB-3111 is also being combined with obinutuzumab (Gazyva) (NCT02569476), and BGB-A317, an investigational PD-1 inhibitor (NCT02795182), in phase I trials for patients with B-cell lymphoid malignancies.

The trials are being sponsored by BeiGene, a biopharmaceutical company with a clinical headquarters in Fort Lee, New Jersey, and a research and development center in Beijing, China.

BGB-3111: Small molecule BTK inhibitor to treat B-cell malignancies. BeiGene website. http://www.beigene.com/pipeline/clinical-candidates/bgb-3111/. Updated 2017. Accessed April 5, 2017.

Tam CS, Opat S, Cull G, et al. Twice daily dosing with the highly specific BTK Inhibitor, Bgb-3111, achieves complete and continuous BTK occupancy in lymph nodes, and is associated with durable responses in patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Presented at: 2016 American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 642. http://ash.confex.com/ash/2016/web- program/Paper96122.html.

The phase I study (NCT02343120) features a dose escalation component followed by an expansion stage in which patients will be assigned to different cohorts based on the histology of their cancer. The trial, which seeks to recruit 235 participants, is open to patients with most B-cell lymphoid malignancies. The study is enrolling patients at The University of Texas MD Anderson Cancer Center in Houston and at centers in Australia, New Zealand, and South Korea.

BGB-3111, a second-generation BTK inhibitor, is being tested in patients with refractory B-cell lymphoid malignancies in an effort to determine whether the novel oral small molecule is a viable therapeutic option and to better understand its pharmacologic properties.

Emerging BTK Inhibitor Tested in B-Cell Malignancies

The genomic landscape of metastatic castration-resistant prostate cancer (mCRPC) is becoming increasingly well defined, with new clinical data emerging to clarify and, in many cases, support the use of poly (ADP-ribose) polymerase (PARP) inhibitors.

“PARP is an important mediator of DNA repair as the DNA strand breaks,” said Celestia S. Higano, MD. “And so, when we have a patient who has an underlying DNA repair problem and we inhibit PARP, we can end up with a situation where there is no DNA repair, leading to cell death.”

Higano discussed emerging strategies to target PARP in prostate cancer during a presentation at the New York GU

 Interdisciplinary Prostate Cancer Congress

 and other Genitourinary Malignancies conference that Physicians’ Education Resource

) hosted March 18 in New York City. She is a professor at the University of Washington School of Medicine and a member of the Clinical Research Division at Fred Hutchinson Cancer Research Center in Seattle.

PARPs, a family of multifunctional enzymes, play a critical role in base excision repair, a process through which single-strand DNA breaks are mended (

). In her presentation, Higano identified other key repair pathways for different types of DNA damage: homologous recombination repair and nonhomologous end joining for double-strand breaks; nucleotide excision repair and translesion synthesis for bulky adducts; and mismatch repair for nucleotide mutations, substitutions, deletions, and insertions.

DNA repair alterations are present in approximately 25% to 30% of cases of mCRPC, Higano said. These include 

, and other gene alterations. Higano stressed that there are 2 ways a patient can develop these alterations: either in tumor DNA, which is observed in about 25% of patients, or in the germ- line setting, which is observed in approximately 12% of patients.

In study results published in Cell in 2015, genomic testing of bone or soft tissue biopsies demonstrated that aberrations of 

 were observed at substantially higher frequencies (19.3% overall) in advanced prostate cancer compared with those in primary prostate cancers.

 The study also determined that the frequency of DNA repair alterations increases with disease progression.

Overall, the study found that 89% of affected individuals harbored a clinically actionable DNA aberration, including 62.7% with aberrations in the androgen receptor, 65% in other cancer-related genes, and 8% with germline alterations.

Olaparib (Lynparza), the first PARP inhibitor to gain the FDA’s approval in 2014 with an indication in recurrent ovarian cancer, is being investigated in prostate cancer under a breakthrough therapy designation based on phase II study data. In the trial, olaparib demonstrated high response rates in patients with mCRPC and DNA repair defects.

The study enrolled 50 patients who were no longer responding to standard treatments, including docetaxel, abiraterone acetate (Zytiga), enzalutamide (Xtandi), or cabazitaxel (Jevtana). Genomic sequencing was performed on tumor biopsies as a requirement of the study. Of the 49 evaluable patients, 16 (33%) had a response to the treatment with olaparib, with 12 receiving the treatment for more than 6 months.

The study concluded that the presence of defects in DNA repair genes found in biopsies of metastatic tumors was associated with a high response rate to olaparib in 14 of 16 patients, including all 7 with loss of BRCA2. “They didn’t really know this until after the study, but 14 out of the 16 responders had DNA repair alterations. This was a pretty small study, but it has prompted a lot of interest in researching PARP inhibitors in prostate cancers,” said Higano.

If these DNA repair alterations are present after treatment with abiraterone, docetaxel, or enzalutamide, there is a higher response rate to olaparib, although 1 challenge is the lack of data regarding the overall survival (OS) benefit for patients with CRPC. However, given the breakthrough designation, “it’s not that difficult to get olaparib for your patients,” Higano commented.

Other PARP inhibitors are also in development for patients with prostate cancer, including niraparib (Zejula), rucaparib (Rubraca), and talazoparib (

). Additionally, there are many combinations studies with PARP inhibitors, and so patients who do not have a DNA repair alteration are not necessarily excluded from the potential benefits of PARP inhibitors, Higano said.

 Ongoing Biomarker-Driven Trials of PARP Inhibitors in mCRPC

HR indicates homologous recombination; mCRPC, metastatic castration-resistant prostate cancer.

One such combination study is the phase I KEYNOTE-365 trial, which is investigating the safety and efficacy of combination therapies with pembrolizumab (Keytruda) in patients with mCRPC (NCT02861573). There will be 3 cohorts in this study, each with approximately 70 participants: cohort A will receive pembrolizumab combined with olaparib, cohort B will receive pembrolizumab combined with docetaxel and prednisone, and cohort C will receive pembrolizumab combined with enzalutamide.

There are some challenges facing the development of PARP inhibitors. One of the problems is that it takes a long time, often 2 to 6 weeks, for the results of tumor biopsies and germline tests to be processed for eligibility for biomarker-driven trials. Despite these challenges, a number of studies of PARP inhibitors driven by DNA repair biomarkers are ongoing. In the phase III, randomized TRITON3 study, investigators will be assessing how patients with mCRPC and evidence of a homologous recombination gene deficiency respond to treatment with rucaparib verses treatment with a physician’s choice of abiraterone, enzalutamide, or docetaxel (NCT02975934). This study is currently enrolling participants who have a deleterious mutation in the 

“The thing that makes this trial stand out from all the others is that most of the other trials require patients to have failed docetaxel, whereas this rucaparib trial allows patients to be treated with rucaparib or a choice of abiraterone, enzalutamide, or docetaxel. In terms of patient accrual, patients are allowed to cross over to the rucaparib arm once they fail in the control arm,” Higano said.

In the phase II Galahad study, investigators are assessing the efficacy, safety, and pharmacokinetics of niraparib in men with metastatic CRPC and DNA repair anomalies (NCT02854436).

“I think it’s become increasingly apparent that we need a thorough family history of cancer that might point to patients with DNA repair defects,” said Higano. As genomic testing for directing targeted therapies becomes more integrated into the standard of care for patients with CRPC and PARP inhibitors show more durable responses in clinical trials, these agents will become increasingly available.

RobinsonD,VanAllenEM,WuYM,etal. Integrativeclinicalgenomicsof advanced prostate cancer [erratum appears in Cell. 2015;162(2):454]. 

. 2015;161(5):1215-1228. doi: 10.1016/j.cell.2015.05.001.

Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. 

. 2015;373(18):1697-1708. doi: 10.1056/NEJMoa1506859.

The genomic landscape of metastatic castration-resistant prostate cancer is becoming increasingly well defined, with new clinical data emerging to clarify and, in many cases, support the use of PARP inhibitors.
 

PARP Inhibitors Attract Growing Interest in Prostate Cancer

Although molecular profiling has established colorectal cancer (CRC) as a complex and heterogeneous tumor type, recent research findings are breaking fresh ground in clarifying the extent of genetic mutations among patients diagnosed with the malignancy and the potential for translating those insights into clinically useful therapies.

The next significant development in the field likely will be the FDA’s much-anticipated decision on whether the PD-1 inhibitor pembrolizumab (Keytruda) gains an indication as a therapy for previously treated patients with microsatellite instability-high (MSI-H) cancers, which is believed to account for approximately 15% of early CRCs and about 4% of metastatic tumors.

 The agency is scheduled to make a decision on the application by June 9; if the ruling is positive, pembrolizumab would be the first immunotherapy approved for CRC.

The potential for checkpoint immunotherapy agents to improve outcomes for patients with gastrointestinal malignancies has been moving forward during the past 2 years, primarily due to indications of efficacy in MSI-H tumors.

In updated phase II findings presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, the overall response rate (ORR) was 57% with pembrolizumab in patients with MMR-deficient advanced CRC (16 of 18 patients) including an 11% complete response rate compared with 0% in patients with MMR-proficient tumors (0 of 25).

 Median progression-free survival (PFS) and overall survival (OS) were not reached after a median 9.3-month follow-up.

Results from that ongoing phase II study prompted the FDA to grant pembrolizumab a breakthrough therapy designation as a potential treatment for patients with MSI-H metastatic CRC in November 2015. The pending application includes clinical trial data from 5 multicohort studies in MSI-H cancers, according to Merck, which is developing the drug.

Positive outcomes for checkpoint blockade agents in MSI-H metastatic CRC have sparked interest not only in single-agent immunotherapy but also in combinations. “Immune checkpoint inhibitors have been found to be beneficial for patients as a single agent if they are MSI high,” said Cathy Eng, MD, a professor of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center in Houston. “That’s really changed the paradigm of care in regard to looking at the benefits of immunotherapy in colorectal cancer.”

Eng said that combination trials pairing check- point blockade agents with targeted therapies are seeking to boost response rates for patients with CRC; she noted the combination of PD-1/PD-L1 pathway agents with MEK inhibition as an area of active research.

In a phase Ib study presented at the 2016 World Congress on Gastrointestinal Cancer, the PD-L1 inhibitor atezolizumab (Tecentriq) was paired with the MEK inhibitor cobimetinib (Cotellic) in heavily pretreated patients with microsatellite stable metastatic CRC.

 The combination demonstrated an investigator-assessed ORR of 17% in 23 patients overall. An ORR of 20% was observed in 22 patients with 

In light of those positive results, a 3-arm phase III trial has been launched that compares the combination of atezolizumab and cobimetinib with atezolizumab monotherapy or with regorafenib (Stivarga) in patients with unresectable locally advanced or metastatic CRC who have received at least 2 prior regimens of cytotoxic chemotherapy.

 The trial is open to patients regardless of MSI or 

 mutation status; however, the estimated enrollment of 360 participants would be capped at 5% for MSI-H patients and at 50% for those with wild-type 

Other combinations under study include the pairing of nivolumab (Opdivo) with ipilimumab (Yervoy) in patients with MSI-H CRC. In findings from the phase II CheckMate-142 study presented at the 2016 ASCO Annual Meeting, the combination demonstrated an investigator-assessed ORR of 33.3% and median PFS at 6 months of 66.6% compared with 25.5% and 45.9%, respectively, for nivolumab monotherapy.

 Additional studies combining the 2 immunotherapy agents are planned.

MSI status is playing an increasingly important role in the treatment of patients with CRC. Testing is often performed at the time of diagnosis in order to “identify patients with Lynch syndrome, direct adjuvant chemotherapy, or determine prognosis,” according to recently updated guidelines on molecular testing in CRC that 4 medical societies jointly issued in February.

 Testing for MSI can be performed through immunohistochemistry to detect the loss of 4 MMR proteins (MLH1, MSH2, PMS2, and MSH6) expressed in tumor cell nuclei or through MSI DNA-based testing.

Study findings show that patients with MSI-H status have a favorable prognosis for OS and disease-free survival depending upon stage of disease; some trial results also suggest that MSI-H patients with early-stage disease do not respond to 5-fluorouracil—based adjuvant chemotherapy.

 Conversely, MSI-H status, which is indicative of a higher mutational load, has been predictive of bene t from checkpoint immunotherapy in study findings from patients with metastatic CRC.

“Every patient with colon cancer needs their MSI tested,” said John L. Marshall, MD, director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer at the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, in an interview. “If a patient is MSI-high in stages I through III, we know their prognosis is good, better in fact, and therefore the role of chemotherapy is less clear.

“In metastatic disease, those patients have a worse prognosis and tend to be right-sided colon cancers but we now have checkpoint inhibitors,” Marshall said. “We are looking for patients with MSI-high colon cancers so that we can identify those who are at familial risk, those who should get adjuvant therapy or not, and those who should get checkpoint inhibitors.”

 in April indicate that the prevalence of germline cancer susceptibility gene mutations is greater than previously believed.

 The study, which was conducted at the Dana-Farber Cancer Institute in Boston, included 1058 patients with CRC who were not preselected for age at diagnosis, personal/family history, MSI status, or MMR deficiency. Germline testing was conducted for 25 genes linked to inherited cancer risk.

The results showed that 9.9% of patients had at least 1 pathogenic mutation, including 3.1% with Lynch syndrome. Non-Lynch syndrome gene mutations were detected in 7% of patients, including BRCA1/2 mutations in more than 1% of patients.

Matthew B. Yurgelun, MD, lead author of the study, said researchers have historically believed that inherited factors account for approximately 3% to 4% of patients with CRC. When researchers included a wider pool of patients, however, a greater incidence of mutations was found, noted Yurgelun, a physician at Dana-Farber and an assistant professor of medicine at Harvard Medical School.

“These individuals were not specifically selected for factors we traditionally associate with inherited risks of cancer,” Yurgelun said in an interview. “For example, these individuals were not specifically selected for being young at the time of their colon cancer diagnosis, they were not specifically selected based on factors in their tumor, or based on any sort of family history of cancer. The fraction of individuals found to have inherited mutations in cancer susceptibility genes was quite a bit higher than what we would have expected in the past.”

The findings raise the question of whether current molecular testing is extensive enough to identify patients who would benefit from targeted therapies. The recently updated guidelines recommend 

 mutational testing for patients who are being considered for anti-EGFR therapy, 

V600 status for prognostic stratification and Lynch screening; and MMR testing for all patients with CRC.

“One of the tricky things from our study is to answer the question of which individuals need germline testing,” said Yurgelun. “We’ve historically recommended germline testing for any CRC patient who has a particularly strong family history of colon cancer; any colon cancer patient with a strong family history of endometrial cancer, ovarian cancer, and other cancers linked to Lynch syndrome; and any CRC patient who has a significant number of colorectal adenomas or other polyps.

“Our study found that if you look beyond Lynch syndrome, which has historically been known as the most common inherited CRC syndrome, you end up finding a lot of inherited mutations and there doesn’t seem to be, at least from our data, a lot of specific factors that tell us which individuals need germline testing,” continued Yurgelun. “It raises the question of whether we should be performing germline testing on all individuals with CRC, which is a pretty slippery slope.

“I think the counterargument to that is that some of these inherited mutations still have a lot of questions behind them, even when we find these mutations, so we’re not quite ready to be recommending germline testing for all individuals with CRC,” he added. “I think we would come up with as many questions as we do answers if we were to do that.”

Marshall believes that broad molecular profiling has the potential to yield clinically useful information and is becoming more common in biomarker-guided trials that seek to match patients with drugs that have proved effective in different histologies.

“I believe this is where the field is going,” Marshall said. “We’re going to want to know this in everyone. But we’re dancing a line right now between what is standard of care and what is research. Our patients with metastatic disease, I think, should all be tested using broad pro ling because we know we’re not going to cure them [but we can] see if they’re eligible for one of these other drugs that are out there under these clinical trials.”

Although differences in treatment outcomes based on tumor sidedness in CRC have been described in oncology research for more than 15 years, the molecular underpinnings of those variations have come into sharp focus as a result of research presented at the 2016 ASCO Annual Meeting.

Retrospective findings from the CALGB 80405 study demonstrated that survival outcomes in patients with KRAS wild-type metastatic colorectal cancer were significantly longer among those with tumors originating on the left versus the right side of the colon.

The median OS was nearly 14 months longer in patients with left-sided tumors compared with right-sided tumors, including a nearly 20-month survival advantage in patients receiving frontline cetuximab (Erbitux) plus chemotherapy and a more than 7-month survival benefit in patients receiving frontline bevacizumab (Avastin) plus chemotherapy.

Overall, researchers found that median OS was 33.3 months for patients with left-sided primary tumors compared with 19.4 months for right-sided tumors. Among patients who received cetuximab, the median OS was 36 months in the left-sided cohort versus 16.7 months in the right-sided group; in the bevacizumab groups, the median OS was 31.4 months for left-sided tumors versus 24.2 months for right-sided malignancies.

Alan P. Venook, MD, the lead investigator on the study, and others in the field believe the tumor-sidedness findings reflect variations in molecular aberrations and that further study is needed to elucidate the differences.

“It is not a function of right versus left side; it’s molecular features that appear to be nonrandomly distributed across the colon,” said Venook, a professor of medicine at the University of California, San Francisco, in an interview. “I am hoping that we will have the opportunity in the next year or 2 to explain not only why patients do better on the left versus right with certain drugs, but also to prospectively understand why that is and how we should be treating patients. Right now, we do very little in terms of biomarker decision making; we decide what not to use instead of what to use. Hopefully, we will do the opposite in the future.”

Marshall is among those researchers seeking to advance understanding of the molecular differences at work in these cancers. At the 2017 Gastrointestinal Cancers Symposium, Marshall and colleagues presented study findings indicating that there are molecular variations between left-sided colon tumors and rectal tumors.

 mutations were found in rectal versus descending colon cancers, while the prevalence of PIK3CA and BRAF mutations was higher in the colon cancers. However, in another study, multivariate analysis found no differences in OS or PFS in patients with left-sided colon cancer versus rectal cancer.

“The reason this is important is because doctors are now thinking clinically about if it is a right-sided or left-sided tumor,” Marshall said in discussing the 2 studies. “We should bundle rectal cancer in with left-sided colon cancer for the moment. These 2 studies determined that we don’t need to additionally stratify for rectal cancers.”

Looking forward, Marshall sees an ongoing need for research into tumor location and molecular features. “A next step includes continuing to conduct prospective studies looking at the molecular characterization of the right side versus left side,” he said. “That’s going to help us in terms of figuring out how to act in a metastatic setting. It’s not clear to me that even with next-generation sequencing that we’re going to find the secret gene.”

Overman MJ, Kopetz S, McDermott RS, et al. Nivolumab ± ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results. Presented at: 2016 ASCO Annual Meeting; June 3-7, 2016; Chicago, IL. Abstract 3501. meetinglibrary. asco.org/content/166455-176.

Kim S-E, Paik HY, Yoon H, Lee JE, Kim N, Sung MK. Sex- and gender-specific disparities in colorectal cancer risk. 

 2015;71(17):5167-5175. doi: 10.3748/wjg.v21.i17.5167.

New data from phase 2 study evaluating Keytruda (pembrolizumab) for the treatment of cancers deficient in DNA mismatch repair show durable responses across a range of cancers [news release]. Kenilworth, NJ: Merck; June 5, 2016. businesswire.com/news/ home/20160605005086/en/Data-Phase-2-Study-Evaluating-KEY- TRUDA%C2%AE-pembrolizumab. Accessed May 15, 2017.

Bendell J, Kim TW, Chee CE, et al. Safety and efficacy of cobimetinib and atezolizumab in a phase 1b study of metastatic colorectal cancer (mCRC). Presented at: ESMO 18th World Congress on Gastrointestinal Cancer; June 29-July 2, 2016; Barcelona, Spain. Abstract LBA-01. doi: org/10.1093/annonc/mdw237.01.

NIH Clinical Trials Registry. A study to investigate efficacy and safety of cobimetinib plus atezolizumab and atezolizumab monotherapy versus regorafenib in participants with metastatic colorectal adenocarcinoma. ClinicalTrials.gov website. Identifier: NCT02788279. Updated April 3, 2017. Accessed May 10, 2017.

Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular biomarkers for the evaluation of colorectal cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. 

 2017;35(13):1453-1486. doi: 10.1200/JCO.2016.71.9807.

Yurgelun MB, Kulke MH, Fuchs CS, et al. Cancer susceptibility gene mutations in individuals with colorectal cancer.

. 2017;35(10):1086-1095. doi: 10.1200/JCO.2016.71.0012.

Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1o) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). Presented at: 2016 ASCO Annual Meeting; June 3-7, 2016; Chicago, IL. Abstract 3504. meetinglibrary.asco.org/content/161936-176.

Marshall J, Lenz HJ, Xiu J, et al. Molecular variances between rectal and left-sided colon cancers. Presented at: 2017 Gastrointestinal Cancers Symposium; January 19-21, 2017; San Francisco, CA. Abstract 522. meetinglibrary.asco.org/content/176344-195.

Salem ME, Yin J, Renfro LA, et al. Rectal versus left-sided colon cancers: Clinicopathological differences observed in a pooled analysis of 4,182 patients enrolled to 8 clinical trials from the ARCAD database. Presented at: 2017 Gastrointestinal Cancers Symposium; January 19-21, 2017; San Francisco, CA. Abstract 675. meetinglibrary.asco.org/content/176249-195.

MSI, which is caused by mismatch repair deficiency (MMR) in the DNA mechanism, is among the genomic markers that are growing increasingly relevant in treatment plan recommendations for patients with CRC. Experts in the field expect that trend to continue, particularly as more knowledge is gained about the correlation between tumor sidedness and molecular aberrations (

Extensive studies into molecular aberrations in colorectal cancer are yielding fresh insights into the potential clinical utility of checkpoint immunotherapies, genetic testing, and tumor-sidedness implications. Experts weigh in on key developments that may change treatment paradigms. 


Genomic Findings Reshaping CRC Field

Despite decades of efforts to improve cytotoxic chemotherapy combinations for patients with lung cancer, we have made very modest improvements in outcomes and the malignancy remains a leading cause of cancer-related death worldwide. Recent advances in immunotherapies that use agents to circumvent critical tumor immune evasive pathways, such as PD-1/PD-L1, have shown promise. Three drugs targeting these pathways are now approved by the FDA for use in patients with non—small cell lung cancer (NSCLC): nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq). However, most patients with NSCLC who are treated with immunotherapy do not respond to these therapies.

At Cleveland Clinic, we are investigating novel treatment options for patients with lung cancer that can increase the likelihood of a response to immunotherapy. This research is funded in part by the Conquer Cancer Foundation of the American Society of Clinical Oncology and the National Cancer Institute. If successful, these efforts will lead to novel strategies that enhance endogenous antitumor immune responses and improve the efficacy of immune checkpoint inhibitors in lung cancer.

One of the key reasons that patients with lung cancers are not able to mount an adequate spontaneous immune response against their cancer is because of the suppression of critical proteins in the tumor that help the immune system recognize tumor cells. This complex orchestration of critical proteins in the tumor results in loss of expression of neoantigens, or nonself proteins, needed for immune recognition of the tumors. For example, some tumor-specific antigens, such as cancertestis family antigens, can induce immune responses. These antigens and the antigen presentation mechanisms are often epigenetically silenced in lung cancer. This suppression allows the tumors to be invisible to the immune system, thereby making immunotherapy ineffective.

The DNA methyl-transferase 1 (DNMT1) enzyme is a critical mediator of such epigenetic silencing. In addition, DNMT1 mediates the epigenetic repression of hundreds of late-differentiation genes in tumor cells. These genes inhibit the MYC function and terminate cell growth and proliferation independent of 

. Thus, DNMT1 is a valid molecular target, and inhibiting DNMT1 can allow termination of cancer cell proliferation by mechanisms independent of 

 and induce expression of tumor-specific antigens.

Decitabine, which depletes DNMT1, is FDA approved to treat myeloid cancers. Decitabine, however, is rapidly eliminated in solid organs by the cytidine deaminase (CDA) enzyme, and thus, the decitabine distribution into solid tissues is trivial, which severely limits the potential of decitabine as an effective lung cancer treatment. This basic pharmacologic limitation cannot be overcome by increasing the dose or by using a continuous infusion because both methods increase the concentration of decitabine in sensitive tissues (eg, bone marrow) to toxic levels, while target solid tissues still receive inadequate exposure.

This limitation can be overcome by combining decitabine with tetrahydrouridine (THU), an inhibitor of CDA. In a preclinical study in murine models, the combination boosted levels of CD8-positive lymphocytes and other immune-priming biomarkers.

Further, in a phase I clinical trial, the addition of THU prolonged the half-life of decitabine from a few minutes to many hours. With such improved bioavailability and with the low Cmax and extended Tmax through solid tissues, this novel combination can provide noncytotoxic epigenetic treatment of solid tumor malignancies.

In collaboration with investigators at the National Institutes of Health, researchers at Cleveland Clinic will be studying this novel pharmacologic approach in the randomized phase II PRECISE trial (NCT02664181).

 The study aims to enroll 60 patients with NSCLC that has progressed after at least 1 prior systemic treatment or targeted therapy, if appropriate. In the experimental arm, patients will receive oral THU at approximately 10 mg/kg followed by oral decitabine at about 0.2 mg/kg plus intravenous nivolumab at 3 mg/kg every 2 weeks until progression. In the comparator arm, nivolumab will be administered at 3 mg/kg every 2 weeks until progression, which is the standard of care for patients with NSCLC who have progressed after receiving chemotherapy. The primary endpoints are objective response and overall response rates.

This multi-institutional clinical trial, which is expected to start enrollment in June, has the potential to help many patients and improve outcomes from treatment with immunotherapy.

Kang K, Rakshit S, Schalper A, et al. Pre-clinical proof of principle of pharmacologically rational non-cytotoxic epigenetic-immunotherapy to treat lung cancer. 

. 2016;34(suppl;abstr e14073). meetinglibrary.asco.org/content/170714-176.

National Institutes of Health Clinical Trials Registry. Pharmacologically rational epigenetic immunotherapy for second line therapy in patients with non-small cell lung cancer (PRECISE). ClinicalTrials.gov website. Identifier: NCT02664181. Updated March 31, 2107. Accessed May 5, 2017.

An epigenetic strategy under study at Cleveland Clinic combines THU, a cytidine deaminase inhibitor, with decitabine and nivolumab (Opdivo) in patients with non-small cell lung cancer. The results of early studies demonstrate that THU may help prime the immune system.

Vol. 18/No. 10 | Oncology Live®

The Hunt for Biomarkers and Better Treatments in Advanced TNBC

Emerging BTK Inhibitor Tested in B-Cell Malignancies

PARP Inhibitors Attract Growing Interest in Prostate Cancer

Genomic Findings Reshaping CRC Field

Cleveland Clinic Researchers Explore Epigenetic Combo as Immunotherapy Booster

Resistance to Coverage for Molecular Testing Panels Illustrates Need for New Policies

Acting on the Genome